11β-hydroxysteroid dehydrogenase (hereinafter, abbreviated as 11β-HSD)1 is an enzyme that converts in cells an inactive form of glucocorticoid (cortisone or 11-dehydrocorticosterone) into an active form of glucocorticoid (cortisol or 11β-corticosterone), and is found to be expressed on the liver, central nerves and the like as well as subcutaneous fat and visceral fat (non-patent documents 1 and 2). Meanwhile, in cells, enzyme 11β-HSD2 is also present that converts an active form of glucocorticoid into an inactivated form. An active form of glucocorticoid is converted in cells from inactive precursor by the action of 11β-HSD1, thereby exercises its effect. Glucocorticoid has been reported to be involved in adipocyte differentiation and to inhibit glycolipid metabolism that is helped by insulin (non-patent document 3). 11β-HSD1 activity and expression level in adipose tissues positively correlate with body-mass index (BMI) or insulin resistance (non-patent document 4). Further, it is reported that a transgenic mouse over-expressing 11β-HSD1 specifically in adipose tissues exhibits a phenotype comprising a combination of major factors of metabolic syndrome, such as visceral fat accumulation, insulin resistance, dyslipidemia, hypertension and fatty liver (non-patent documents 5 and 6). By contrast, it is reported that, in an 11β-HSD1 knockout mouse, an inactive form cannot be converted to an active form and as a result, the induction of the group of gluconeogenic enzymes attributable to the burden of high-fat food does not occur in the liver, which acts suppressively on hyperglycaemia due to obesity (non-patent document 7). It is also reported that decreased blood triglyceride, elevated HDL cholesterol, and improved insulin resistance were observed (non-patent document 8). From these findings, active form of glucocorticoid produced excessively by 11β-HSD1 is considered to cause the onset of a metabolic disease such as diabetes, insulin resistance, diabetes complication, obesity, dyslipidemia (hyperlipidemia), hypertension, and fatty liver, or a metabolic syndrome pathology which comprises a series of these metabolic diseases. Therefore, a selective inhibitor of 11β-HSD1 is believed to be useful for treating or preventing the above pathologies.
Heretofore, many compounds have been reported for the purpose of inhibiting 11β-HSD1 activity. The examples of reported compounds include compounds having a spiro structure (patent documents 1 to 4), adamantane derivative (patent document 5), sulfonamide derivative (patent document 6), pyrazole derivative (patent document 7), isooxazole derivative (patent document 8), triazole derivative (patent document 9), tetrazole derivative (patent document 10), pyridine derivative (patent document 11), pyrimidine derivative (patent document 12), piperidine derivative (patent document 13), pyridazine derivative (patent document 14), pyrrolidine derivative (patent document 15), thiazole derivative (patent document 16), thiophene derivative (patent document 17), lactam derivative (patent document 18) and the like.
On the other hand, a compound having an adamantyl group on the nitrogen atom (1-adamantyl azetidin-2-one derivative) has been reported. Examples include a compound having action of inhibiting cholesterol absorption (non-patent document 9); a compound having an action of enhancing release of neurotransmitter (patent document 19); and a compound having an antiviral action (patent document 20). Further, 1-adamantyl azetidin-2-one derivative has been reported as a subject of reaction and synthesis studies (non-patent document 10, non-patent document 11, non-patent document 12, non-patent document 13, patent document 21, non-patent document 14, non-patent document 15, non-patent document 16, non-patent document 17). Such are the reports on a compound having 1-adamantyl azetidin-2-one derivative skeleton, and most of them are reported as a compound not having substituent on the 4th position of azetidin-2-one ring, which is different from the 1-adamantyl azetidin-2-one derivative of the present invention. As for the compound which is the closest to the Compound of the present invention (compound No. 79 in the non-patent document 9), the substituent of the 3rd position of azetidin-2-one ring is different from the 1-adamantyl azetidin-2-one derivative of the present invention. Further, there is no description nor suggestion that 1-adamantyl azetidin-2-one derivative inhibits 11β-HSD1 activity, and it has not been known at all that azetidin-2-one skeleton compound is useful as an agent for preventing and/or treating diabetes, insulin resistance, diabetes complication, obesity, dyslipidemia, hypertension, fatty liver, or metabolic syndrome.